Pharmacogenomics In Drug Therapy And Interaction: The Role Of Cytochrome P450
- Author:
Chin-Eng Ong
;
Yan Pan
;
Kai-Hung Tiong
;
Beow-Chin Yiap
;
Eng-Lai Tan
;
Peter Pook
;
Joon-Wah Mak
- Publication Type:Review
- Keywords:
Pharmacogenomics, Pharmacogenetics, Drug Interaction, Drug Therapy, Cytochromes P450
- From:International e-Journal of Science, Medicine and Education
2008;2(supp1):6-10
- CountryMalaysia
- Language:English
-
Abstract:
Pharmacogenomics (or pharmacogenetics),
the study of the effects of genetic differences on a
person’s response to drugs, can help in optimizing drug
efficacy and minimizing adverse drug reactions.
Interperson difference in drug metabolism is one of the
important consequences of such genetic variation. This
variation is determined in part by mutations in
cytochrome P450 enzymes (CYPs). IMU is part of a
major collaborative research project in the area of
phamacogenetics and drug metabolism. Working
together with USM and UiTM, our group has, since
2000, generated useful population database on genetic
polymorphism of various CYP isoforms. We have
successfully genotyped three major ethnic groups,
Malay, Indian and Chinese for their allelic frequency of
important isoforms. These include CYP2D6, CYP2C9,
CYP2C8 and CYP2A6. Data generated so far
collectively have contributed to our effort in mapping
and constructing genomic database for Malaysian
population.
Since early 2002, our research has been focusing on
developing in vitro methods in studying the functional
consequences of genetic polymorphism of CYP enzymes.
Using site-directed mutagenesis, CYP mutants, carrying
nucleotide changes as reported in known alleles in
human populations, were generated and expressed in
E. coli system, and the expressed recombinant proteins
were characterized using enzyme assays to determine
the functional consequences of mutations. We have
established a series of HPLC (high performance liquid
chromatography)-based and fluorescence-based assays
to investigate CYP activities. Assays that have been
developed include tolbutamide methylhydroxylase,
paclitaxel 6a-hydroxylase, dextromethorphan
O-demethylation, testosterone 6b-hydroxylation and
coumarin 7-hydroxylase assays. These assays serve as
activity markers allowing comparison of catalytic
activities of mutant proteins generated. Another focus
of our work is to use the developed assays as a screening
tool to investigate drug-herb interactions. This was
achieved by co-incubation of herbal extracts and active
constituents with the probe substrates in the assays followed by characterization of the kinetic behaviors of
the enzymes involved using various pharmacokinetic
parameters such as Km, Vmax, IC50 and Ki. This work is
currently carried out with collaboration from the
Institute for Medical Research (IMR) and is supported
by MOSTI’s eScienceFund under RM9. It is envisaged
that this screening work will give us insights on the
potential of the commonly used herbs to cause
pharmacokinetic interactions with other drug
substrates, and allow us to elucidate the mechanisms
involved in the interactions.
- Full text:W020150928394750915567.pdf
